Endophilin A2 protects against renal fibrosis by targeting TGF‐β/Smad signaling

Abstract

Renal fibrosis underlies all forms of end-stage kidney disease. Endophilin A2 (EndoA2) plays a role in nephrotic syndrome; however, its effect on renal fibrosis remains unknown. Here, we demonstrate that EndoA2 protects against kidney interstitial fibrosis via the transforming growth factor-β (TGF-β)/Smad signaling pathway. Mouse kidneys with fibrosis or kidney biopsy specimens from patients with fibrotic nephropathy had lower levels of EndoA2 protein expression than that in kidneys without fibrosis. In vivo overexpression of EndoA2 with the endophilin A2 transgene (EndoA2 Tg ) notably prevented renal fibrosis, decreased the protein expression of profibrotic molecules, suppressed tubular injury, and reduced apoptotic tubular cells in the obstructed kidney cortex of mice with unilateral ureteral obstruction (UUO). In vivo and in vitro overexpression of EndoA2 markedly inhibited UUO-or TGF-β1induced phosphorylation of Smad2/3 and tubular epithelial cells dedifferentiation. Furthermore, EndoA2 was coimmunoprecipitated with the type II TGF-β receptor (TβRII), thus inhibiting the binding of the type I TGF-β receptor (TβRI) to TβRII. These findings indicate that EndoA2 mitigates renal fibrosis, at least partially, via modulating the TGF-β/ Smad signaling. Targeting EndoA2 may be a new potential therapeutic strategy for treatment of renal fibrosis.

Altenusin, a fungal metabolite, alleviates TGF-β1-induced EMT in renal proximal tubular cells and renal fibrosis in unilateral ureteral obstruction

“…TGF-β1 plays an important role in EMT and kidney fibrosis [ 31 ]. The upregulation of EMT and fibrosis markers can be found under the activation of TGF-β1 through its downstream signaling pathways [ 7 , 32 ]. TGF-β1-induced morphology changes the renal proximal tubular cells into a fibroblast-like structure representing EMT [ 7 ].…”